Effects of estrogen and progesterone and the role of mast cells in pregnancy

The term estrogen generally refers to estrogen estradiol (E2.)  This steroid hormone is induced when gonadotropin releasing hormone (GnRH) is released in the hypothalamus and acts on the pituitary gland.  This in term releases follicle stimulating hormone (FSH) which acts on the follicle, resulting in the release of estrogen.  Secretion of GnRH is stimulated by a protein called kisspeptin. High levels of estrogen or progesterone inhibit the secretion of kisspeptin.  Hormone levels are regulated in this way. 
 

Estrogen is mostly produced by the ovaries and placenta, but is made in smaller amounts by the liver, adrenal glands, breasts and fat cells.  E2 promotes secondary female sex characteristics, increases metabolism, increases fat stores, stimulates endometrial and uterine growth, promotes vaginal lubrication, thickens the vaginal wall, maintains integrity of blood vessels and skin, reduces bone resorption and increases bone formation.  It also promotes effective coagulation by increasing platelet adhesion.  E2 increases HDL cholesterol and triglycerides while decreasing LDL and fat deposition.  It balances salt and water retention, increases cortisol levels, reduces bowel motility, and increases the amount of cholesterol found in bile.  It also promotes wound healing and has anti-inflammatory properties.

With progesterone, E2 promotes and maintains the uterine lining, as well as increasing the amount of oxytocin released during pregnancy.  Estrogen surge induces the secretion of luteinizing hormone, triggering ovulation. 

Progesterone (P4) also regulates salt and water balance, prepares the uterus for implantation, affects vaginal tissue and cervical mucus to prevent sperm from entering the uterus during pregnancy, suppresses menstruation, decreases maternal immune response to pregnancy, decreases contractility of uterine smooth muscle and inhibits lactation during pregnancy.  With prolactin, progesterone prepares breast tissue for milk production after childbirth.  Drop in progesterone levels during pregnancy is thought to be a key step in induction of labor.  Progesterone also has a variety of other regulatory effects, though the exact nature of these functions is not entirely clear.

Progesterone receptors on cells can be increased by the action of estrogen.  Furthermore, the activity of progesterone is amplified by the presence of estrogen.

The importance of mast cells in reproductive biology has been known for over sixty years.  Mast cells express receptors for both estrogen and progesterone.  These hormones together attract mast cells from the peripheral tissues to the uterus.  Furthermore, they induce the maturation of mast cells and directly cause degranulation in a dose dependent manner.  Together, they induce more degranulation than individually.

During pregnancy, embryo-derived histamine releasing factor induces secretion of histamine by uterine mast cells.  Histamine is also secreted by endothelial and decidual cells.  Mast cells have a protective role in ensuring successful embryo implantation.  Mast cells also positively influence the growth of blood vessels and participate in tissue remodeling so that the pregnancy can be sustained through placental growth and adequate blood supply. Degranulation increases uterine contractility through histamine and serotonin action.  Allergic activation causes significant contractions. 

In placentas from intrauterine growth retardation, mast cell concentrations are significantly decreased.  When mast cell numbers are diminished, the cells formed following implantation are at different stages, and are smaller and delayed.  Pregnancies with this feature generally do not survive.

In some cases, severe allergic reactions are thought to be responsible for preterm labor.  Additionally, degranulation in pre-eclampsic patients caused increased vascular resistance, likely from vasoconstriction by histamine.  Asthmatic pregnant women are known to be at a higher risk of pre-eclampsia.  People with other mast cell diseases should likewise by monitored for this condition.

Estrogen and progesterone levels can be correlated to symptoms in asthma.  Postmenopausal women taking hormone replacement therapy have a higher risk of new onset asthma.  30-40% women have asthma with more symptoms during the premenstrual period when estrogen and progesterone concentrations are dynamic.  Many women with mast cell disease likewise report more degranulation when menstruating.  Mast cell density in non-uterine tissues is much higher in pregnant woman, likely due to the higher hormone concentrations. 

A paper released in 2013 referenced a 2001 study by Metcalfe and Akin that found that women with SM were more likely to have preterm labor and delivery.  However, a 2011 study in Spain found that only 3/45 (6.7%) women delivered prematurely.  The rate of preterm birth in the general Spanish population is 7.4%.  It is unclear whether this change was due to increasing understanding of SM and more effective treatment, or due to the changes in diagnostic criteria between these studies.

The presence of mast cells is crucial for healthy pregnancy.  However, excessive activation can cause contractions and increased symptoms for pre-eclampsia patients.  The most recent study demonstrates that overwhelmingly, women with SM deliver healthy babies at the appropriate time.

References:

Woidacki, K., Jensen, F., Metz, Zenclussen, A. (2013). Mast cells as novel mediators of reproductive processes. Front. Immunol. 10.

Woidacki, K., Popovic, M., Metz, M., Schumacher, A., Linzke, N., Teles, A., et al. (2013). Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death Dis. 4, e462.

Metcalfe, D. D., and Akin, C. (2001). Mastocytosis: molecular mechanisms and clinical disease heterogeneity. Leuk. Res. 25, 577–582.

Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S et al. (2010). Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One 2010; 5: e14409.

Matito, A., et al.  (2011.) Clinical impact of pregnancy in mastocytosis: A study of the Spanish network on mastocytosis (REMA) in 45 cases.  Int Arch Allergy Immunol; 156: 104-111.